Purpose: Central precocious puberty (CPP) is mostly idiopathic, however, familial cases of CPP and evidence of genetic factors on pubertal timing by genome-wide association studies suggest genetic causes of CPP. Molecular defects in six genes (KISS1, KISS1R, LIN28A, LIN28B, TAC3, and TACR3) have been known to cause early activation of the hypothalamic-pituitary-gonadal axis. Therefore, this study investigated genetic defects in these six genes and the effect of gonadotropin-releasing hormone agonist (GnRHa) treatment on final adult height (FAH) in girls with CPP.
Subjects and Method: Of 133 girls with CPP diagnosed at Asan Medical Center, 60 girls who reached FAH were evaluated. Seven of them showed intracranial lesions including pilocytic astrocytoma, hamartoma, hydrocephalus, meningitis, acute disseminated encephalomyelitis, and Rathke’s cleft cyst. Bone age (BA) was determined by the Greulich-Pyle method, and predicted adult height (PAH) was estimated using the Bayley-Pinneau method. DNA analyses including the KISS1, KISS1R, LIN28A, LIN28B, TAC3, and TACR3 genes, were performed in the remaining 73 girls with idiopathic CPP whose DNA samples were available. Forty-one of them (56.2%) had a family history of CPP or early puberty.
Results: The mean age of thelarche, BA, and chronological age (CA) at diagnosis were 7.3, 10.1, and 7.8 years. The basal and peak luteinizing hormone (LH) levels by GnRH stimulation tests were 1.5 and 18.1 IU/L, respectively. In patients who had reached FAH, the duration of therapy was 2.5 ± 0.8 years, and the CA, BA, and height at the end of GnRHa therapy were 10.9 ± 0.5 years, 11.8 ± 0.4 years and 148.2 ± 4.5 cm, respectively. The age at menarche was 12.2 ± 0.6 years, and the mean interval between the interruption of therapy and menarche was 1.35 ± 0.45 years (range, 0.6 ? 2.5 years). FAH significantly increased after therapy compared to PAH at diagnosis (160.9 ± 4.5 cm vs. 156.8 ± 7.1 cm, p < 0.001). Height gain was 4.1 cm and subjects’ FAH was similar to their target height (159.5 ± 3.6 cm). There were no significant differences in FAH and age at menarche between organic and idiopathic CPP (p = 0.24, 0.28, respectively). Of the 73 girls who underwent DNA analyses, only one girl harbored a heterozygous variant of p.L210I in the TACR3 gene, which is located in the third transmembrane domain of the neurokinin B receptor (NK3R), known to have local stimulatory action on kisspeptin secretion. The variant was predicted to be possibly damaging by PolyPhen-2. It was inherited from the subject’s mother whose age at menarche was 12 years.
Conclusion: Almost patients achieved increased FAH and the appropriate timing of menarche after GnRHa therapy. This study indicates that mutations in candidate genes of CPP are a rare cause of CPP, even in patients with family members with early pubertal timing. Other genetic defects, modifier genes, or environmental influences may play a crucial role in pubertal timing.